1. Field of the Invention
This invention relates to pharmaceutical formulations of desoxyepothilones and methods for their preparation and use.
2. Description of Related Art
The class of polyketides known as epothilones has emerged as a source of potentially therapeutic compounds having modes of action similar to paclitaxel (see, e.g., Cowden, C. J. and Paterson, I., “Synthetic chemistry. Cancer drugs better than taxol?” Nature 1997, 387, 238-9). Interest in the epothilones and epothilone analogs has grown with the observations that certain epothilones are active against tumors that have developed resistance to paclitaxel (Harris, C. R., Balog, A., et al., “Epothilones: microtubule stabilizing agents with enhanced activity against multidrug-resistant cell lines and tumors,” Actualites de Chimie Therapeutique 1999 25, 187-206) as well as reduced potential for undesirable side-effects (Muhlradt, P. F. and Sasse, F., “Epothilone B stabilizes microtubuli of macrophages like taxol without showing taxol-like endotoxin activity” Cancer Res. 1997 57 (16), 3344-6). Among the epothilones and epothilone analogs being investigated for therapeutic efficacy are epothilone B and the semi-synthetic epothilone B analogs, BMS-247550, also known as “azaepothilone B” (see, e.g., McDaid et al., “Validation of the Pharmacodynamics of BMS-247550, an Analogue of Epothilone B, during a Phase I Clinical Study,” Clin Cancer Res 2002 8 (7), 2035-43), and BMS-310705.
Desoxyepothilone B (1), also known as “epothilone D” is another epothilone derivative having promising anti-tumor properties viz. paclitaxel that is being investigated for therapeutic efficacy (Su, D.-S., Meng, D., et al., “Total synthesis of (−)-epothilone B: an extension of the Suzuki coupling method and insights into structure-activity relationships of the epothilones,” Ang. Chemie, Int. Ed. Eng. 1997 36 (7), 757-759; Chou, T. C., Zhang, X. G., et al., “Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel,” Proc Natl Acad Sci USA 1998 95 (26), 15798-802; Harris, C. R., Kuduk, S. D., et al., “New Chemical Synthesis of the Promising Cancer Chemotherapeutic Agent 12,13-Desoxyepothilone B: Discovery of a Surprising Long-Range Effect on the Diastereoselectivity of an Aldol Condensation,” J. Am. Chem. Soc. 1999 121 (30), 7050-7062.; Chou, T.-C., O'Connor, O. A., et al., “The synthesis, discovery, and development of a highly promising class of microtubule stabilization agents: curative effects of desoxyepothilones B and F against human tumor xenografts in nude mice,” Proc. Natl. Acad. Sci. USA 2001 98 (14), 8113-8118; Danishefsky et al. US 2002/0058817 A1 (2002); Martin, N. and Thomas, E. J., “Total syntheses of epothilones B and D: applications of allylstannanes in organic synthesis,” Tetrahedron Letters 2001 42 (47), 8373-8377; and Danishefsky et al. US 2002/0058286 A1 (2002)). This compound has also demonstrated less toxicity than epothilones having 12, 13-epoxides, such as epothilone B or BMS-247550.

The epothilones in general, and the desoxyepothilones in specific, have poor aqueous solubility; and current epothilone formulations typically include a castor oil derivative solubilizing agent sold under the trade name CREMOPHOR® (polyethoxylated castor oil; BASF Aktiengesellschaft) to enhance solubility. CREMOPHOR® has been associated with patient discomfort and toxicity, in part due to allergic reactions. Therefore, it would be preferable to provide enhanced formulations of desoxyepothilones that do not require CREMOPHOR®. Further, the 16-member ring system of desoxyepothilones is susceptible to hydrolytic degradation upon storage in aqueous media. There is thus an unmet need for formulations of desoxyepothilones that are chemically and physically stable to long-term storage and that provide chemically and physically stable, well-tolerated solutions upon dilution into aqueous media prior to administration.